Houston native Allison Rosen ​​​was 32 when she learned in June 2012 that the suddenly painful digestive problems she’d been having for a month or two were caused by a tumor blocking her colon. “The first thing you think is, ‘I want this foreign thing removed from my body,’” she says, describing how she felt when she learned she had colon cancer. “I wanted it out.”

All three oncologists she consulted, however, urged Rosen, who was a research laboratory manager at the Baylor College of Medicine in Houston, to delay surgery. They recommended her treatment start with close to six weeks of chemotherapy and radiation to first shrink the tumor and kill any cancer cells that might be circulating in her body. “They explained it would make surgery easier on my body and reduce long-term side effects,” she says.

Even though she trusted her health care team, Rosen knew that the wait to have the tumor removed would be difficult. Initial scans showed a 5-inch mass blocking the lower part of her digestive tract—and nearby lymph nodes were inflamed, suggesting the cancer had already spread. Until the date of her surgery, she would not know if the tumor was responding to treatment. “Fear of the unknown was in the back of my mind,” she says, noting that she sought out support from professionals and people who had similar experiences with their treatment. “The psychological aspect made me say, ‘I need to talk to a patient, a survivor, a professional or all of the above who understands what I’m going through to help me deal with it.’”

When she woke from surgery on Sept. 4, 2012, Rosen learned that her tumor had shrunk to less than half an inch. As part of the surgery, Rosen also had a temporary ileostomy, which would divert digested food from the lower part of her small intestine into a pouching system outside her body. This would give her lower digestive tract time to heal from the surgery.

Rosen had more chemotherapy from October 2012 to February 2013, followed by another surgery to reverse the ileostomy. By April 2013, her cancer was in remission. In March 2020, she marked seven years cancer-free at her 40th birthday celebration—a joyous gathering of family and friends from around the country held just a few weeks before Texas issued stay-at-home orders in response to the coronavirus pandemic.

Rosen is one of a growing number of people whose treatment for cancer includes neoadjuvant therapies—chemotherapy, hormone therapy or radiation—delivered before surgery. Research on these presurgical treatments has shown that patients with certain cancers experience better outcomes, including improved quality of life and longer periods of remission and survival, compared to those who have treatments after surgery. In addition, neoadjuvant treatment can sometimes boost a patient’s chances of completing a full course of the recommended therapy or allow a previously inoperable tumor to meet the criteria for surgery.

“We know that there are some tumors that have very high risk of recurrence after surgery … and we know that leads to poor survival,” says Padmanee Sharma, a medical oncologist at the University of Texas MD Anderson Cancer Center in Houston, who was not involved in Rosen’s care. “That’s the reason to consider neoadjuvant therapy, to try to decrease recurrence and improve survival.”

Uprooting the Seeds of Metastasis

The most common form of pancreatic cancer, called pancreatic ductal adenocarcinoma (PDAC), furnishes a stark case in point. By the time people are diagnosed with PDAC, at least 80% of them have tumors too large or widespread to be surgically removed. Even among the fraction of people whose pancreatic tumors are localized enough for surgery, the risk of recurrence is high. “Surgery treats the primary tumor, but not the metastatic seeds that we can’t see,” says surgical oncologist Herbert Zeh at the University of Texas Southwestern Medical Center in Dallas.

When Zeh was in medical school, doctors recommended that people with pancreatic cancer who qualified for surgery have the operation immediately. The Whipple procedure, named after the surgeon who pioneered it in the 1930s, is an extensive surgery in which surgeons remove the tumor, as well as the head of the pancreas, the gallbladder and portions of the small intestine, bile duct and sometimes the stomach. In this complex and invasive procedure, surgeons shift and reassemble the organs that remain, hoping to preserve some digestive function.

When Zeh embarked on his surgical training in 1994, most people spent 12 weeks or more recovering from Whipple surgery before they were strong enough to begin the recommended course of chemotherapy. That gave micrometastatic seeds—miniscule traces of cancer in the body that might not show up on a scan or be visible to a surgeon’s trained eye—a three-month head start, Zeh says.

Robotic surgical techniques, including some that Zeh pioneered, have reduced complications from Whipple surgery, leading to quicker recovery. Yet to this day, nearly 50% of patients who start their treatment regimen with the complex surgery never get chemotherapy. The operation is too physically draining and often plagued with complications. Conversely, close to 90% of people with PDAC who get neoadjuvant chemotherapy and radiation proceed to surgery. Those are much better odds, notes Zeh, given that long-term survival has very little to do with the primary tumor and everything to do with those micrometastases that might be present but are not visible. “I never say always—that’s not a very academically honest approach—but I think 97% of patients with pancreatic cancer should have chemo first.”

The Sandwich Strategy

At Southwestern Medical, most of Zeh’s pancreatic cancer patients who are candidates for surgery start with three months of chemotherapy and radiation before the procedure and three months of chemotherapy after—though regimens may vary among medical centers. This postsurgical course of chemotherapy boosts the chance that any cancer cells that survived neoadjuvant treatment and weren’t removed during surgery are eliminated. A similar approach is used in colon cancer and in some types of breast cancer.

Having surgery after initial treatment offers an added benefit since pathological evaluation of a tumor and the surrounding tissue after removal can help physicians learn more about the cancer and its response to treatment. Such analysis can confirm whether cancer cells were replaced with scar tissue, whether nearby lymph nodes are merely inflamed or cancerous, and whether any cancer cells in the tumor itself survived. Depending on what the pathological analysis reveals, the health care team could tailor their recommendations for postsurgical treatments accordingly by exploiting the vulnerabilities in the tumor, depending on its response—or lack of response—to earlier treatments.

The best-case scenario—what’s known as a pathological complete response, in which pathologists find no evidence of surviving cancer cells after neoadjuvant therapy—has been associated with a favorable prognosis across a wide range of malignancies. Among them are many types of breast and digestive cancers, including esophageal and rectal cancers. “Over the years, we’ve learned that patients with a complete disappearance of tumor or lymph node involvement for invasive breast cancer have the best overall survival and greatest benefit from chemo,” says Douglas Yee, director of the Masonic Cancer Center at the University of Minnesota in Minneapolis. Yee is the co-chair of the agent selection committee for the I-SPY 2 trial, which is evaluating neoadjuvant therapies, including immunotherapy, for locally advanced breast cancer.

The Role of New Treatments​

Researchers are testing whether targeted therapies and immunotherapies can be useful prior to surgery.

Although considered largely experimental, the use of targeted therapy or immunotherapy delivered before surgery to remove a tumor is a growing area of research. The American Society of Clinical Oncology (ASCO) named refinement of surgical treatment of cancer as the 2020 Advance of the Year, highlighting studies on neoadjuvant therapy using immunotherapy and targeted therapy.

ASCO described a study published in the July 1, 2019, Lancet Oncology, which analyzed 35 patients with stage III melanoma that was positive for a mutation in the BRAF gene. Patients were given a combination of two oral targeted therapies, Tafinlar (dabrafenib) and Mekinist (trametinib), prior to surgery. In the study, 30 of the 35 patients had a treatment response, and 49% of the patients had a pathological complete response, which means there were no traces of cancer in the removed tissue. In addition, the treatment shrank the tumors, making surgery easier in almost half the cases, ASCO notes.

Other research cited by ASCO included a phase II study published in the July 1, 2019, Lancet Oncology that examined three different dosing regimens for Yervoy (ipilimumab) and Opdivo (nivolumab) as neoadjuvant treatment for stage III melanoma. The researchers were analyzing effectiveness and toxicity to pinpoint an ideal dose for patients prior to surgery. The next step will be to compare the preferred neoadjuvant dosing schedule with the standard of care, which provides immunotherapy after surgery, the study notes.

In patients with metastatic renal cell carcinoma, care can include surgery to remove the kidney followed by targeted treatments or immunotherapy. However, two studies suggest some patients with metastatic kidney cancer may be able to avoid surgery and proceed with the targeted therapy Sutent (sunitinib). The CARMENA trial, which was first published in 2018 in the New England Journal of Medicine, compared the use of Sutent alone or following surgery in 450 patients with metastatic renal cell carcinoma. Researchers found the median overall survival was longer for patients receiving only Sutent—18.4 months compared with 13.9 months for those who received the drug after surgery. Another trial included 99 patients who were followed for more than three years. The study, published in the Feb. 1, 2019, issue of JAMA Oncology​, noted that patients who received Sutent prior to surgery showed no improvement in progression-free survival compared to patients who took Sutent after surgery. However, median overall survival was 32.4 months for those with a metastatic renal cell carcinoma who delayed surgery and took Sutent compared with 15 months for those who had surgery right away.​

​More Time and Space

By shrinking large, invasive tumors, neoadjuvant therapy can also change the scope of surgery—from a mastectomy to a lumpectomy, for example, or in the case of rectal surgery, lower a patient’s risk of urinary and sexual side effects. “The pelvis is very narrow, technically difficult,” says surgical oncologist Julio Garcia-Aguilar, a colorectal cancer surgeon at Memorial Sloan Kettering Cancer Center in New York City. “Making the tumor smaller gives the surgeon more room to maneuver in the pelvis and remove the tumor.” Rectal cancer is also characterized by early metastatic spread, and surgery can significantly diminish quality of life, so surgery alone “does not give excellent results,” says Garcia-Aguilar.

People with breast cancer have already seen profound shifts in surgical recommendations as data from studies launched in the 1960s revealed that a radical mastectomy—removing the breast, chest muscle and nearby lymph nodes—conferred no survival benefit compared to a total mastectomy, which spares the chest muscle and possibly some of the underarm lymph nodes. “Systemic therapy has been the most important part of improving cancer patient survival,” says Yee.

For people with locally advanced breast cancer, receiving chemotherapy or hormone therapy before surgery confers comparable survival with reduced surgical scope, when compared to starting with surgery and then proceeding to chemotherapy or hormone therapy. Even so, the psychology of waiting months for a tumor to respond to neoadjuvant therapy can be intense, Yee says.

Still, people with breast cancer can use the time during which they receive neoadjuvant therapy to more fully consider their surgical treatment options, Yee says. He recommends patients interview multiple surgeons as they weigh their options for breast reconstruction, for example. “There’s no disadvantages to doing chemo first; it gives people time to think.”

In locally advanced rectal cancer, physicians often administer a full course of chemotherapy and radiation before surgery, a protocol known as total neoadjuvant therapy (TNT). This approach represents a shift from providing such systemic therapies before and after surgery. TNT has been more widely accepted over the past decade as research showed that rectal cancer patients who received a full course of therapy before surgery were more likely to complete a full course of treatment, had higher rates of complete response and suffered less severe side effects such as diarrhea, fatigue and neutropenia.

Since the transition to TNT at Memorial Sloan Kettering began in 2007, Garcia-Aguilar and his colleagues have shown that among people with stage II and III rectal cancer who had TNT, 32% to 35% had pathological complete response. “Seeing that some tumors seem to be gone, we started to think about whether we can just treat the rectal cancer with neoadjuvant therapy alone, and preserve the rectum,” says Garcia-Aguilar.

For these patients, holding off on rectal surgery—and not having to deal with a temporary or permanent ileostomy or colostomy, and the risk of sexual and urinary dysfunction—holds tremendous appeal. The risk is that cancerous cells may still exist, threatening survival. To lessen this danger, rectal cancer patients at Memorial Sloan Kettering who defer surgery undergo active surveillance, with endoscopies and physical exams every three months in the first year after treatment, every four months in the second year and every six months through year five. “We don’t have diagnostic tools that can tell with 100% certainty that the tumor is gone or not,” says Garcia-Aguilar. “The only way we can [defer surgery] is if patients are willing to come back regularly to make sure that the tumor is gone.”

While researchers and clinicians hope neoadjuvant therapy will make surgery unnecessary, these treatments are already making surgery less intrusive and improving survival and quality of life for patients. In addition, scientists are studying whether newer treatments like immunotherapy and targeted therapy can be used in neoadjuvant settings to provide less invasive options.

“It is an active research question,” says Yee, the breast cancer researcher. “Maybe someday, [some patients] will get away with maybe no surgery at all. But that’s still in the future.” 

Sharon Tregaskis is a science writer living in Ithaca, New York.

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